Automatic sample handling apparatus



y 1966 H. BARUCH ETAL Re. 26,055

AUTOMATIC SAMPLE HANDLING APPARATUS Original Filed July 2. 1962 2Sheets-Sheet 1 V VIIIIIIIIIIIIIIIIII/IIIIII/IIIII/A \\\\\\\\})?J --W 7V,

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INVENTORS HANS BARUCH BY ERIK w. ANTHON ATTORNEYS July 5, 1966 BARUCH TRe. 26,055

AUTOMATIC SAMPLE HANDLING APPARATUS Original Filed July 2. 1962 2Sheets-Sheet 2 47 F I [Er--2- INVENTORS 46 HANS BARUCH ERIK w. ANTHON BYSAZW #M ATTORNE V5 United States Patent 26,055 AUTOMATIC SAMPLE HANDLINGAPPARATUS Hans Baruch, Berkeley, and Erik W. Anthon, Kensingtou,

Calif., assignors, by mesne assignments, to Warner- LambertPharmaceutical Company, Morris Plains, NJ. Original No. 3,192,969, datedJuly 6, 1965, Ser. No.

207,111, July 2, 1962. Application for reissue July 12,

1965, Ser. No. 471,798

13 Claims. (Cl. 14190) Matter enclosed in heavy brackets appears in theoriginal patent but forms no part of this reissue specification; matterprinted in italics indicates the additions made by reissue.

The present invention relates to improvements in an automatic samplehandling apparatus, and more particularly to an apparatus fortransferring a measured quantity of sample or like liquid from oneposition to another.

In certain types of analytical procedures, large numbers of routinedeterminations must be carried out. Particularly applicable are thoseemployed in biochemical, physiological and medical laboratories wherematerials such as blood, blood serum, tissue serum, urine or othermaterials are tested and/or analyzed. These tests are particularlysuited for automation because the analytical procedures are repeated 2.large number of times. However, certain of the procedural steps requiredhave been somewhat ditiicult to automate in comparatively simple andreliable equipment capable of providing the necessary continuedaccuracy.

One of. the problems encountered in automating such analyticalprocedures is that of accurately measuring and handling liquid sampleswhere a large number of samples are desired to be handled by the samepiece of equipment. One of the ditlicultics encountered is the requiredwashing of the piece of equipment used so as to prevent contamination bypreviously handled samples. One way of handling this problem is toprovide means for washing the unit between samples, but this generallyrequires additional equipment. Thus the present invention provides asimpler and more economic solution to this problem, Where the washingrequirement is reduced or eliminated.

In most analytical procedures, it is necessary to add a certain quantityof diluent or reagent to the sample as it is processed. in the presentinvention, this diluent or reagent can be used not only to provide thenecessary step of addition thereof, but also used to clean out themechanism for measuring and delivering a fixed quantity of sample.

Accordingly, it is the primary object of the present invention toprovide an apparatus for transferring a measured quantity of sample fromone position to another which is completely automatic in its operation.

Another object of this invention is to provide an apparatus of thecharacter described in which an exceedingly accurate measure of samplecan be taken up and dispensed.

A further object of the invention is to provide an apparatus of thecharacter described which is self-cleaning and substantially eliminatesany contamination from previously handled sample material.

Still another object of the invention is the provision of an apparatusfor transferring a measured quantity of sample from one position toanother in which rather small liquid samples are accurately measured andhandled automatically.

Still another object of the invention is the provision of an apparatuscapable of taking up and delivering a measured quantity of liquid sampletogether with a measured quantity of another liquid by utilizing aunique combination of pumps and a valve mechanism whereby the taking upand delivery of liquid may be completely and automatically controlledthrough the valve operation alone.

Re. 26,055 Reissuecl July 5, 1966 "ice Further objects and advantages ofour invention will be apparent as the specification progresses and thenew and useful features of our automatic sample handling apparatus Willbe fully defined in the claims attached hereto.

The preferred forms of our invention are illustrated in the accompanyingdrawing forming part of this description, in which:

FIGURE 1 is a schematic view of an embodiment of the inventionillustrating the broad aspect thereof; and

FIGURE 2 is a schematic view illustrating in detail a preferred form ofthe invention.

While we have shown only a broad form and a preferred form of ourinvention, it should be understood that various changes or modificationsmay be made within the scope of the claims attached hereto withoutdeparting from the spirit of the invention.

In its broad form, the invention combines a probe or pipette capable oftaking up a measured quantity of liquid sample or the like, incombination with pump means for controlling liquid in the probe and aliquid supply source for providing diluent, reagent or the like andwashing out the probe so as to leave the probe clean for the nextoperation.

Referring to FIGURE 1 in detail, the broad aspect of the invention isillustrated by the apparatus 11 comprising a suitable source of sampleat a sample site 12 wherein sample is carried into a container 13, aprobe or pipette 14 positioned at the sample site, a pump 16 for movingfluid in and out of the probe, a liquid supply source 17 and a valve 18for regulating the fluid flow provided by the pump.

The sample site 12 is here shown as occupied by one of the containers13, and the containers 13 are carried on a turntable 19 so as to providemovement into and out of operative relation to the probe. Alternatively,other means may be used to move the samples, if desired. As here shown,the probe 14 is also moved in a reciprocating motion along its axis asindicated by arrow 21. In this way, the probe may be moved to operativeposition at a drain 22 or into position at a delivery site 23. All ofthese movements may be mechanized together through suitablereciprocating mechanical means (not shown) so that this operation of thedevice is suitable for automation.

The pump 16 is similar to a hypodermic needle type pump, and itcomprises a barrel 24 and a piston 26 sliding therein. Thus when valve18 is closed, movement of piston 26 causes fluid to be taken into orforced out of the passage within the probe 14, the barrel 24 and a line27 associated therebetween.

As best seen in FIGURE 1, line 27 has a narrow area 28 which serves torestrict the flow of sample into line 27 so that during operation of theapparatus with valve 18 in communication with liquid supply source 17,the barrel 24 of the pump fills with liquid from the liquid supplysource while the probe is filling with sample. The narrow area may alsobe used as a gauge to provide an accurately determined volume of sample.

Thus in operation of the device of FIGURE 1, the probe 14 is positionedat the sample site and valve 18 is opened while the piston 26 is in theclosed or upward position. Then the piston 26 is drawn downward to drawin reagent, diluent or other liquid while the sample moves slowly intothe probe and through the narrow area and up into line 27, but themovement is stopped before sample reaches the junction 29 of the pumpand line 27. The valve is then turned to the closed position and theprobe is moved to the drain. The piston 26 is then moved upwards anamount sufiicient to expel the sample into the drain while retaining ameasured quantity of reagent. The probe is moved back to the sample tubeand a measured quantity of sample is then drawn in by controlledmovement of the pump. With the system thus charged with measuredquantities of reagent and sample, the probe is moved into operativeposition at the delivery site and the pump operated to discharge all ofthe sample and the measured amount of reagent. It is seen that thereagent is last delivered and washes the probe in preparation for thenext operation.

Other methods of operation are also possible. For example, the operationcould be simplified by beginning the cycle as mentioned above with thevalve open, but stopping the operation of the pump when the desiredamount of sample is taken up. The valve is closed and the probe moved tothe delivery site. The pump is then operated to discharge the samplefollowed by reagent or diluent. The ratio of reagent to sample isdetermined by the flow characteristics of the system and the size of theconstriction 28. In this operation, the drain 22 is not used.

The operation could also be accomplished by begin ing with the valveopen, and drawing in excess sample. The valve is then closed and theprobe moved to the drain. With this p:.sition obtained, the piston 26 ismoved upwards to expel suflieient sample through the probe so that theinterface between the sample and the reagent is in the narrow area. Thenthe probe is moved into operative position within the delivery site andpiston moved upwards to expel all of the sample followed by a desiredamount of reagent or diluent that has been drawn into the pump barrel24.

While the embodiment shown in FIGURE 1 is operative for the purposerequired, it is often desired to utilize an apparatus in which themeasurement of the sample and of the diluent or other liquid is muchmore accurately controlled. Such a system is provided in the embodimentshown in FIGURE 2, in which a special valve and a plurality of pumps areused for the purpose. In addition, the embodiment of FIGURE 2 shows howa reagent dispenser may be included in addition to the sample deliverysystem with the reagent dispensing system operating through the samevalve as the sample delivery system, thus being programmed to operatesimultaneously therewith.

Thus in the embodiment illustrated in FIGURE 2, there is shown anapparatus 31 capable of transferring a measured quantity of sample fromone position to another while simultaneously providing an accuratelymeasured quantity of diluent and an accurately measured quantity ofreagent. As here shown, the device comprises a probe or pipette 32.pumps 33 and 34, reagent [for] or diluent container 36, and a valve 37which provides communication between the pumps and either pressure line38 or vacuum line 39. In addition, the pump 41 may be included in thesystem for drawing reagent from reagent container 42 and delivering itto the sample either as the sample is added at the delivery site or atany other desired position.

All of the pumps 33, 34 and 41 are similarly constructed and adapted tooperate by means of air pressure or vacuum with the air pressure causingthe pump to move in one direction and the vacuum causing it to move inreverse direction. Thus each pump comprises a housing 43 enclosingchambers 44 and 46 with chamber 44 adapted to contain air under pressureor vacuum on one side of a piston 53 with the other side vented.Movement of piston 59 activates a plunger 47 which reciprocates inchamber 46 and is sealed through the housing to prevent lluidcommunication between the chambers. Thus plunger 47 adjusts the volumein chamber 46 and ellects movement of liquids into and out of eachchamber depending upon the valve positions.

In order to accurately adjust the volume of liquid taken into thechambers 46. stop means 48 are provided to limit the movement of theplungers 47. In order to adjust the stop means 48. ls'nurlcd handle 4')is rotated so as to more stop means 43 through its scaled threadedengagcment with the housing 43. The setting may be accurately adjustedon a suitable gauge 51 which may include a vernier scale (not shown) orany other conventional measuring scale for providing accurate measurements.

The valve 37 may be any valve structure capable of providing thecommunications shown for the position illustrated in the drawing and theposition shown in phantom in the drawing. For example, any two-position,three-way ganged valve structure would be functional. As shown in theschematic representation of valve 37 in FlGURE 2 of the drawings. asuitable combined valve may be constructed in which a ported valvemember 52 is slidable from one position to the other in a suitablyported housing 53. A very suitable valve and mechanism for operating thesame is described and claimed in the co-pcnding application Serial No.183,506 of Erik W. Anthon filed March 29, 1962, now US. Patent No.3,I99,538 entitled Valve and assigned to the assignee of the presentapplication.

In operation, the device has the valve position shown when liquid isbeing discharged from the probe or pipette 32 into a receivingcontainer. This discharge is effected because air pressure from the aircompressor 54 passes into the valve from line 38, through the valve inpassage 56, and through line 57 to the chamber 44 of pump 33 which is incommunication with the chambers 44 of pumps 34 and 41 through lines 53.With chambers 44 pressurized, the pistons 50 and associated plungers 47are moved downwardly to cause chambers 46 to be decreased in volume sothat liquid is discharged from each chamber. In this way, the sampletaken into the probe or pipette is first discharged, and then diluentfollows to wash out the sample. More specifically, the diluent isdischarged from chamber 46 of pump 34 through line 59, passage 61, line62, chamber 46 of pump 33 and thence through line 63 and probe 32.

While the diluent in the sample is discharged. reagent is also beingdischarged from pump 41 by virtue of the fact that air pressure ismoving the plunger 47 thereof downward and decreasing the volume of itschamber 46. As chamber 46 of pump 41 is decreased in volume, reagentflows out through line 64, passage 66, line 67 and out through reagentprobe 68. The reagent probe may be positioned either at the samplereceiving site or at any other station depending upon the desiredprogramming to be used.

After sample, diluent and reagent are delivered as explained above,valve element 52 is positioned in the position shown in phantom, inFIGURE 2 by any suitable means. As here shown, the block is moved byreciprocating member 69 which is operated by an eccentric 7'1 through amotor which is activated by suitable relays (not shown) in order tobring the valve operation in proper timed relation with any othercomponents that may be added to carry out other analytical processsteps.

When the valve is positioned at the opposite extreme the passages 56,61, 66 and 72 are raised as shown in phantom on the drawing, and thechambers 44 of the pumps 33, 34 and 41 are connected to the suction sideof the pump through loop passage 72 in the valve and line 39. With thisconnection. the plungers 47 are drawn upwardly and the chambers 46 areincreased in volume so as to suck in fluid and fill the chambers.Chamber 46 of pump 33 is in communication with the pipette or probewhile its other line is cut oil. In this way. the amount of liquid takenup into the pipette is exactly the same as the change in volume ofchamber 46 as adjusted on the gauge 51 of said pump. In similar fashion,pump 34 is in communication with the reagent or diluent container 36 andthe amount of liquid taken into chamber 46 of this pump is againregulated by its gauge.

It is important in the operation of this mechanism that the chambers 46and associated lines he kept filled with diluent at all times so thatthe pumps operate accurately through incompressible liquids. Similarly,pump 41 has its chamber 46 and associated lines filled at all times withreagent. Thus the quantity of reagent taken up by the pump on the up orvacuum stroke is measured accurately by its gauge 51. The timing isarranged so that suflicient time is allowed for the liquids to be drawnin the chambers with the plungers moved to the full position possible incontact with the associated stop means 48. In this way, full volumes ofliquid are taken up and delivered.

The probe 32 may be moved from the sample site to the delivery site byany suitable mechanism such as the Materials Handling Apparatusdescribed and claimed in the United States Patent application Serial No.61,206 filed October 7, 1960, now U.S. Patent No. 3,178,266, by Erik W.Anthon, an inventor in the present application. respect to the probe asshown in FIGURE 1.

Accordingly, it is seen that we have provided an apparatus capable ofproviding the rather difficult process steps of taking up and deliveringmeasured quantities of sample. In addition, the apparatus is constructedto be self-cleaning to keep the apparatus free of contamination, and iscapable of providing exceedingly accurate quantities of the fluidshandled.

We claim:

[1. An apparatus for transferring a measured quantity of liquid samplefrom one position to another, comprising a probe adapted for taking up aliquid sample at a reservoir source, a first pump means connected tosaid probe and formed for drawing liquid sample into the probe, areservoir for holding a wash liquid, a second pump means operativelyconnected to said reservoir and said probe and formed for taking up saidwash liquid and delivering the wash liquid through the probe, and meansfor controlling said first and second pumps and directing delivery ofsaid Wash liquid from said second pump through said first pump and saidprobe whereby the following wash liquid will rinse the liquid samplefrom said probe] 2. An apparatus for transferring a measured quantity ofliquid sample from one position to another, comprising a probe fortaking up liquid sample, a first pump means having a first chamberconnected to said probe and formed for taking up a measured quantity ofliquid sample into the probe, a reservoir for holding diluent to beadded to the liquid sample, a second pump means having a second chamberoperatively connected to said reservoir and said probe and formed fortaking up a measured quantity of diluent, and control means forsimultaneously effecting actuation of said first and second pumps [and]for taking up said liquid sample and diluent and then directing deliveryof diluent from said second pump chamber directly through said firstpump chamber and said probe whereby the diluent while effecting thedesired dilution washes liquid sample from the probe and thereby cleansthe same.

3. The apparatus defined in claim 2, in which each one of the pumpchambers [means] is formed with [a chambar and] a plunger movable intoand out of the chamber to provide a differential volume in the chamber.

4. The apparatus defined in claim 3, in which each one of the pump meansis also provided with an adjustable stop for accurately adjusting thelength of stroke of the plunger so as to selectively vary saiddifferential volume in the chamber.

5. The apparatus defined in claim 4, in which an air compressor isprovided to actuate the plunger of each of said pump means by operativeconnection of the compression side and vacuum side of the compressor tothe pump means through said control means.

6. An apparatus for transferring a measured quantity of liquid samplefrom one position to another, comprising a first probe for taking upliquid sample, a first pump means for drawing liquid sample into thefirst probe,

Alternatively, the samples may be moved with a first reservoir forholding a supply of wash liquid to be added to the liquid sample, asecond pump means for taking up wash liquid from said first reservoirand delivering said wash liquid through said first probe, a second probefor delivering reagent to the sample, a second reservoir for holdingreagent to be added to the sample, a third pump means for taking in ameasured quantity of reagent and delivering said reagent through saidsecond probe, and control means for effecting actuation of said first,second and third pump means and for directing delivery of wash liquidfrom said second pump through said first pump and said first probewhereby the wash liquid rinses the liquid sample from said first probe.

7. An apparatus for transferring a measured quantity of liquid samplefrom one position to another, comprising a first probe for taking upliquid sample and delivering said sample and a diluent, a first pumpmeans for taking up a measured quantity of liquid sample into the probe,at first reservoir for holding diluent to be added to the sample, asecond pump means for taking up a measured quantity of diluent, a secondprobe for delivering reagent to the sample, a second reservoir forholding reagent to be added to the sample, a third pump means for takingin a measured quantity of reagent and delivering said reagent throughsaid second probe, and control means for effecting actuation of saidfirst, second and third pump means and directing delivery of diluentfrom said second pump through said first pump and said first probewhereby the diluent washes liquid sample from the first probe andthereby cleans the same.

8. The apparatus defined in claim 7, in which each one of the pump meansis formed with a chamber and a plunger movable into and out of thechamber to provide a difierential volume in the chamber [determined bythe length of stroke of the plunger in the chamber].

9. The apparatus defined in claim 8, in which each one of the pump meansis also provided with an adjustable stop for accurately adjusting thelength of stroke of the plunger so as to selectively vary saiddifferential volume in the chamber.

10. The apparatus defined in claim 9, in which an air compressor isprovided to actuate the plunger of each of said pump means by operativeconnection of the compression side and vacuum side of the compressor tothe pump means through said control means.

11. An apparatus for transferring a measured quantity of liquid samplefrom a supply site to a sample receiving site, comprising probe meansproviding a conduit having an end adapted for contacting a body ofliquid sample at the supply site for taking a measured quantity ofliquid sample into said conduit, reservoir means for containing a supplyof other liquid to be expelled through said conduit after said sample,pump means operatively connected to said probe means and reservoir meansand formed for taking in a measured quantity of liquid sample, and valvemeans interposed between said probe means and said reservoir and formedfor cooperating with said pump means to expel said measured quantity ofliquid sample from said probe means followed by a desired quantity ofsaid other liquid, said probe means being selectively movable topositions at the sample supply site and the receiving site and at adrain; and said valve means and pump means cooperate to take in anexcess quantity of sample when said probe means is at the sample supplysire, and cooperate to expel sample from said probe means when thelatter is at said drain so as to leave a desired quantity of sample insaid probe means, and cooperate to expel said desired measured quantityof sample followed by a desired quantity of said other liquid when saidprobe means is at said receiving site.

[12. An apparatus as described in claim 11 and wherein said probe meansis selectively movable to positions at the sample supply site and thereceiving site and at a drain; and said valve means and pump meanscoopcrate to take in an excess quantity of sample when said probe meansis at the sample supply site, and cooperate to expel sample from saidprobe means when the latter is at said drain so as to leave a desiredmeasured quantity of sample in said probe means, and cooperate to expelsaid desired measured quantity of sample followed by a desired quantityof said other liquid when said probe means is at said receiving site.]

13. An apparatus as described in claim [12] II, and wherein theoperative connection of said pump means to said reservoir is formed witha liquid passage having a minimum cross-sectional area, and wherein theconduit in said probe means is formed with a portion having across-sectional area considerably smaller than said minimumcross-sectional area of said passage, whereby said pump means will becapable of drawing in liquid sample through said probe and the otherliquid from said reservoir simultaneously and in a desired ratiodetermined by the relative minimum cross-sectional areas of said conduitand passage.

[14. An apparatus for separating a measured quantity of sample from abody of liquid sample and adding another liquid thereto, comprising anelongated hollow probe having an end formed with an orifice therethroughcommunicating with the interior of the probe, a reservoir adapted forcontaining other liquid, a conduit systcm adapted for filling with saidliquid and formed for operatively connecting said reservoir to theinterior of said probe, intake means operative for selectivelyincreasing the effective volumetric capacity of said conduit system fordrawing a measured quantity of liquid sample into said probe when saidend is dipped into a body of liquid sample, and discharge meansconnected to said conduit system and formed for effecting pumping of adesired quantity of other liquid from said reservoir into said conduitsystem after operation of said intake means, whereby said measuredquantity of sample and a desired quantity of said other liquid will beexpelled from said probe through said orifice] 15. The apparatus definedin claim 2, in which an air compressor is provided to actuate said firstand second pump means and said control means comprises a combinedmnlli-port air and liquid valve having a power driven linearlyreciprocable valve member operable for simultaneously cflecting theaforesaid connecting of said compressor to the pump means and providing,required liquid comnmnication betwccn said reservoir, pump means andprobe.

16. The apparatus defined in claim 3, in which said reservoir containsdiluent at atmospheric pressure.

References Cited by the Examiner The following references, cited by theExaminer, are of record in the patented file of this patent or theoriginal patent.

UNITED STATES PATENTS 2,661,885 12/1953 McBean 14l-105 X 2,807,2139/1957 Rosen l03-38 X 3,012,863 12/1961 Feichtmeir 23--253 3,127,0623/1964 Feichtmeir et al. 222-135 3,193,148 7/1965 Anthon 222334 X3,197,285 7/1965 Rosen 141105 X OTHER REFERENCES Feichtmeir et aL:Journal of Clinical Pathology, Williams and Wilkins Co., U.S.A., 1961,vol. 35, No. 4, R131 A3, pp. 378482.

LAVERNE D. GEIGER, Primary Examiner.

H. BELL, Assistant Examiner.

